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Kim, Jung, Sohn, and Im: Quantitative Structure Activity Relationship between Diazabicyclo-[4.2.0]octanes Derivatives and Nicotinic Acetylcholine Receptor Agonists
Original Article

Korean J Physiol Pharmacol 2009;13(1):55-59.

Published online: 17 February 2009

DOI: https://doi.org/10.4196/kjpp.2009.13.1.55

Quantitative Structure Activity Relationship between Diazabicyclo-[4.2.0]octanes Derivatives and Nicotinic Acetylcholine Receptor Agonists

Eun Ae Kim, Kyoung Chul Jung, Uy Dong Sohn, Chaeuk Im

College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea

Corresponding to: Chaeuk Im, College of Pharmacy, Chung-Ang University, 221, Heuksuk-dong, Dongjak-gu, Seoul 156-756, Korea. (Tel) 82-2-820-5603, (Fax) 82-2-816-7338, (E-mail) Chaeukim@cau.ac.kr

Copyright © 2009 Korean J Physiol Pharmacol

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Three dimensional quantitative structure activity relationship between diazabicyclo[4.2.0]octanes and nicotinic acetylcholine receptor (hα4β2 and hα3β4) agonists was studied using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). From 11 CoMFA and CoMSIA models, CoMSIA with steric and electrostatic fields gave the best predictive models (q2=0.926 and 0.945, r2ncv=0.983 and 0.988). This study can be used to develop potent hα4β2 receptor agonists with low activity on hα3β4 subtype.

Keywords: Diazabicyclo[4.2.0]octanes, CoMFA, CoMSIA, Nicotinic acetylcholine receptors (nAChRs)

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Fig. 1.
The superimposed structures of aligned training set.
kjpp-13-55f1.tif
Fig. 2.
CoMSIA contour map of steric field for the hα4β2 subtype.
kjpp-13-55f2.tif
Fig. 3.
CoMSIA contour map of electrostatic field for the hα4β2 subtype.
kjpp-13-55f3.tif
Fig. 4.
CoMSIA contour map of steric field for the hα3β4 subtype.
kjpp-13-55f4.tif
Fig. 5.
CoMSIA contour map of electrostatic field for the hα3β4 subtype.
kjpp-13-55f5.tif
Table 1.
Structures and biological activity of 3-N-substituted diazabicyclo[4.2.0]octanes
kjpp-13-55f6.tif
Table 2.
Structures and biological activity of 8-N-substituted diazabicyclo[4.2.0]octanes
kjpp-13-55f7.tif
Table 3.
CoMFA and CoMSIA results of the training set
Field∗ q2† N‡ SEP§ r2ncv|| SEE F∗∗ Contributions
S E H D A
hα4β2 subtype                      
 CoMFA                      
  S 0.832 6 0.375 0.967 0.166 147.107 1        
  E 0.819 6 0.390 0.966 0.168 143.232   1      
  SE 0.892 6 0.301 0.987 0.104 382.064 0.534 0.466      
 CoMSIA                      
  SE 0.926 6 0.249 0.983 0.120 285.165 0.128 0.872      
  SEH 0.695 6 0.506 0.987 0.103 393.914 0.077 0.567 0.356    
  SED 0.866 6 0.335 0.978 0.134 227.120 0.056 0.454   0.490  
  SEA 0.884 6 0.312 0.978 0.136 220.764 0.117 0.782     0.101
  SEDA 0.833 6 0.374 0.973 0.151 178.867 0.048 0.395   0.506 0.050
  SEHD 0.595 1 0.608 0.980 0.129 248.687 0.046 0.339 0.199 0.415  
  SEHA 0.650 6 0.542 0.986 0.110 344.311 0.067 0.422 0.356   0.156
  SEHDA 0.605 5 0.576 0.987 0.104 386.129 0.034 0.249 0.226 0.363 0.127
hα3β4 subtype                      
 CoMFA                      
  S 0.787 6 0.518 0.948 0.255 91.574 1        
  E 0.830 6 0.462 0.969 0.197 157.454   1      
  SE 0.934 6 0.288 0.985 0.139 319.679 0.512 0.488      
  CoMSIA                      
  SE 0.945 6 0.262 0.988 0.125 399.560 0.152 0.848      
  SEH 0.688 6 0.627 0.979 0.162 234.901 0.084 0.529 0.387    
  SED 0.900 6 0.354 0.975 0.179 191.750 0.061 0.426   0.513  
  SEA 0.871 6 0.402 0.976 0.174 202.120 0.148 0.773     0.079
  SEDA 0.868 5 0.408 0.972 0.189 171.724 0.057 0.404   0.484 0.055
  SEHD 0.717 4 0.600 0.981 0.154 259.610 0.038 0.306 0.204 0.452  
  SEHA 0.669 6 0.645 0.975 0.176 197.341 0.074 0.368 0.367   0.190
  SEHDA 0.749 4 0.571 0.983 0.147 287.861 0.034 0.216 0.232 0.388 0.129

∗ Fields used, S=steric, E=electrostatic, H=hydrophobics, D=H-bond donor, A=H-bond acceptor;

† q2, cross-validated correlation coefficient from leave-one-out (LOO);

‡ N, optimum number of components;

§ SEP, standard error of prediction;

|| 2ncv, non-cross-validated correlation coefficient;

SEE, standard error of estimate;

∗∗ F, F-test value.

Table 4.
CoMSIA actual and predicted activity (pEC50) of the training set
No hα4β2 subtype h α3β4 subtype No hα4β2 subtype hα3β4 subtype
Actual Predicted Residuals Actual Predicted Residuals Actual Predicted Residuals Actual Predicted Residuals
1 7.15 7.37 −0.22 7.32 7.17 0.15 20 6.96 7.04 −0.08 6.08 6.00 0.08
2 6.48 6.54 −0.06 6.59 6.54 0.05 21 7.68 7.73 −0.05 8.10 8.22 −0.12
3 7.89 7.86 0.03 7.54 7.73 −0.19 22 6.44 6.39 0.05 6.80 6.79 0.01
4 7.62 7.78 −0.16 7.60 7.36 0.24 23 8.21 8.00 0.21 8.36 8.24 0.12
5 6.82 6.63 0.19 7.12 7.29 −0.17 24 6.39 6.41 −0.02 5.77 5.63 0.14
6 6.00 6.07 −0.07 6.02 6.11 −0.09 25 7.43 7.60 −0.17 5.86 5.89 −0.03
7 7.92 8.03 −0.11 8.00 8.15 −0.15 26 6.67 6.71 −0.04 5.82 5.80 0.02−0.11
8 8.11 7.84 0.27 8.09 7.91 0.18 27 6.75 6.90 −0.15 6.47 6.58  
9 7.12 7.05 0.07 6.96 7.05 −0.09 28 6.87 6.95 −0.08 6.53 6.52 0.01−0.04
10 8.14 8.09 0.05 8.14 8.06 0.08 29 6.70 6.58 0.12 6.69 6.73  
11 7.33 7.29 0.04 7.15 7.20 −0.05 30 5.66 5.90 −0.24 5.59 5.53 0.06−0.17
12 5.72 5.72 0.00 6.31 6.20 0.11 31 5.71 5.92 −0.21 5.25 5.42  
13 6.89 6.92 −0.03 6.74 6.56 0.18 32 6.96 7.02 −0.06 6.10 6.08 0.02−0.01
14 5.57 5.60 −0.03 5.35 5.41 −0.06 33 6.76 6.73 0.03 6.62 6.63  
15 5.66 5.56 0.10 5.96 6.17 −0.21 34 5.83 5.78 0.05 4.63 4.51 0.12
16 5.30 5.32 −0.02 5.62 5.58 0.04 35 6.47 6.54 −0.07 5.13 5.16 −0.03
17 6.21 6.20 0.01 6.91 6.94 −0.03 36 5.11 5.06 0.05 4.20 4.28 −0.08
18 5.87 5.64 0.23 5.55 5.66 −0.11 37 5.96 5.98 −0.02 5.36 5.28 0.08
19 6.19 6.14 0.05 5.85 5.83 0.02              
Table 5.
CoMSIA actual and predicted activity (pEC50) of the test set
No hα4β2 s u btype hα3β4 subtype
Actual Predicted Residuals Actual Predicted Residuals
T1 7.09 7.05 0.04 6.96 7.05 −0.09
T2 5.72 5.85 −0.13 6.00 5.82 0.18
T3 7.00 7.00 0.00 6.41 6.60 −0.19
T4 6.74 6.55 0.19 5.24 5.26 −0.02
T5 5.85 5.70 0.15 5.81 5.98 −0.17
T6 7.12 7.11 0.01 5.72 5.95 −0.23
T7 5.77 5.77 0.00 5.53 5.37 0.16
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